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Internal Medicine Vol.47 □ ORIGINAL ARTICLE □ Preventive Effect of Sulfamethoxasole-trimethoprim on Pneumocystis jiroveci Pneumonia in Patients with Interstitial Pneumonia Tatsuji Enomoto 1,2,ArataAzuma2, Aki Matsumoto 2, Takahito Nei 2, Kazue Fujita 2, Kumiko Hattori 1,2, Yoshinobu Saito 2, Shinji Abe 2, Jiro Usuki 2 and Shoji Kudoh 2 Abstract Background Pneumocystis jiroveci pneumonia (PCP) is a potentially fatal complication in interstitial pneu- monia patients receiving glucocorticoid therapy. Prophylaxis of PCP during glucocorticoid therapy is an im- portant issue in the treatment of interstitial pneumonia. Objective We evaluated the prophylactic effect of sulfamethoxasole-trimethoprim (TMP-SMX) in interstitial pneumonia patients receiving glucocorticoids. Methods We retrospectively analyzed 74 interstitial pneumonia patients who received glucocorticoid ther- apy. Results Seven of the 74 patients developed PCP. At the time of diagnosis of PCP, the mean duration of glucocorticoid therapy was 71 days and the mean daily dose of prednisolone was 37 mg. Among the 7 pa- tients, the circulating CD4+ lymphocyte count was 370/μl on average and it was over 200/μl in 3 cases. The PCP patients showed a significant reduction of the lymphocyte count at 4 weeks after initiation of steroid therapy. None of the patients who received prophylactic TMP-SMX therapy developed PCP even if the CD4+ lymphocyte count was less than 200/μl. Conclusion Interstitial pneumonia patients receiving glucocorticoid therapy can benefit from TMP-SMX prophylaxis against PCP. Development of PCP cannot be ruled out in patients with a CD4+ lymphocyte count of greater than 200/μl. Key words: interstitial pneumonia, pneumocystis pneumonia, circulating CD4+ lymphocyte count, prophy- laxis with trimethoprim-sulfamethoxazole, beta-glucan (DOI: 10.2169/internalmedicine.47.0402) stitial pneumonia, prophylactic intervention against infection Introduction may lead to a better outcome of glucocorticoid/immunosup- pressant therapy. Although glucocorticoids and immunosuppressants are In this study, we retrospectively evaluated the efficacy of widely used for the treatment of idiopathic interstitial pneu- trimethoprim-sulfamethoxazole (TMP-SMX) for prophylaxis monia (1), as well as that associated with connective tissue of PCP during glucocorticoid and/or immunosuppressant diseases and vascular disorders (2), glucocorticoid/immuno- therapy for interstitial pneumonia. suppressant therapy has adverse effects such as the oc- curence of opportunistic infections in the lungs, including Materials and Methods Pneumocystis jiroveci pneumonia (PCP), other fungal infec- tions, and cytomegalovirus infection (3, 4). Because of the This study was a retrospective analysis of 74 patients with risk of opportunistic infection during the treatment of inter- interstitial pneumonia (IP) who were admitted to the Depart- １Department of Respiratory Medicine, Tokyo Metropolitan Hiroo General Hospital, Tokyo and ２Division of Pulmonary Diseases, Infection, and Oncology, Nippon Medical School, Tokyo Received for publication June 23, 2007; Accepted for publication September 8, 2007 Correspondence to Dr. Arata Azuma, [email protected] 15 DOI: 10.2169/internalmedicine.47.0402 Table 1. Clinical Features of Patients with Pneumocystis jiroveci Pneumonia ment of Respiratory Medicine at Nippon Medical School matomyositis, 1 with systemic sclerosis, 3 with Sjogren syn- Hospital, and who received more than 0.5 mg/kg of prednis- drome, and 3 with microscopic polyangitis), pneumoconiosis olone with or without immunosuppressants for more than in 1 patient, and chronic hypersensitivity pneumonia in 1 three weeks between July 1997 and September 2003. We patient. evaluated the following clinical parameters: age, sex, under- Fourteen (18.9%) of the 74 patients developed opportunis- lying disease, body mass index, smoking status, diabetes tic pulmonary infection: 7 developed PCP, 3 had cytomega- mellitus, the dose and duration of glucocorticoid therapy, lovirus pneumonia, 1 developed aspergillus pneumonia, 3 use of immunosuppressants, the white blood cell count be- had expanded MRSA pneumonia, and 3 developed sepsis. fore and 4 weeks after the initiation of glucocorticoid ther- The ten patients without PCP infection were excluded from apy, the results of pulmonary function tests before therapy, this study. We only evaluated the first infection in each pa- and the response to prophylaxis with trimethoprim- tient. All 7 patients showed high-resolution computed to- sulfamethoxazole (TMP-SMX). In the IP patients who de- mography findings consistent with PCP. Two patients were veloped PCP, we also evaluated the white blood cell count, positive for pneumocystis on PCR of sputum samples, two circulating CD4+ lymphocyte count, and plasma level of had positive findings on microscopic examination of BALF beta-D-glucan at the time of diagnosis of PCP. samples, and five were positive for pneumocystis by PCR of The diagnostic criteria for PCP were: 1) appropriate find- BALF samples (including 2 patients who were positive on ings on high-resolution computed tomography, and 2) detec- both examinations). tion of Pneumocystis jiroveci by microscopic examination or We compared the 7 patients who developed PCP (PCP by a positive polymerase chain reaction (PCR) assay of spu- group) with the 57 patients who did not develop any oppor- tum and bronchoalveolar lavage fluid (BALF) samples (5). tunistic infection (control group) (Table 1). Age, sex, body Sputum and BALF samples were stained with Papanicolaou mass index, smoking status, results of pulmonary function stain, May-Giemsa stain, and Grocott’s stain for microscopic tests, presence of diabetes mellitus, use of steroid pulse ther- examination. apy, and use of immunosuppressants did not differ signifi- Differences between pairs of groups were examined for cantly between the two groups. However, the initial dose of statistical significance with the χ2 test or one-factor ANOVA. glucocorticoids was significantly different between the PCP Differences among three groups were examined for statisti- group and the control group patients with or without TMP- cal significance with repeated measures ANOVA. SMX prophylax (trimethoprim 80 mg-sulfamethoxazole 400 mg/day). In the control group, 15 of the 57 patients received Results prophylactic therapy with TMP-SMX, while none of the pa- tients in the PCP group received TMP-SMX prophylaxis. The seventy-four patients with interstitial pneumonia com- The white blood cell count and neutrophil count before prised 36 men and 38 women with a mean age of 64 years glucocorticoid therapy were significantly different between (range: 23-85 years). The underlying diseases were idi- the PCP and control groups. However, the lymphocyte count opathic pulmonary fibrosis in 20 patients, idiopathic intersti- four weeks after initiation of glucocorticoid therapy was not tial pneumonias other than idiopathic pulmonary fibrosis in significantly lower in the PCP group than in the control 24 patients, interstitial pneumonia related to collagen vascu- group (Table 2). Despite this, changes of the lymphocyte lar disease in 28 patients (5 with rheumatoid arthritis, 2 with count were significantly different among the three groups systemic lupus erythematosus, 14 with polymyositis/der- i.e., the PCP group, control patients with prophylaxis, and 16 DOI: 10.2169/internalmedicine.47.0402 Table 2. White Blood Cell Subsets in Patients with Pneumocystis jiroveci Pneumonia Table 3. Cases of Pneumocystis jiroveci Pneumonia control patients without prophylaxis (p<0.001 by repeated Table 4. Laboratory Data at the Time of Diagnosis of PCP measures ANOVA). The 7 patients who developed PCP had a mean age of 64 years (range: 55-76 years) and they consisted of three men and four women. Their underlying diagnoses were nonspe- cific interstitial pneumonia (n=2), interstitial pneumonia re- lated to polymyositis/dermatomyositis (n=3), interstitial pneumonia related to systemic sclerosis (n=1), and intersti- tial pneumonia related to microscopic polyangitis (n=1) (Ta- ble 3). The initial dose of glucocorticoid (prednisolone) was 30-100 mg/day, the average initial dose of prednisolone was 55 mg/day, and the cumulative dose was 1.530-16.859 g, and the mean cumulative dose was 5.551 g. The duration of glucocorticoid therapy was 38-175 days, with a mean dura- tion of 71 days. The dose of glucocorticoid at the time of The PCP group had a lower lymphocyte count (mean: diagnosis of PCP was 25-55 mg/day, with a mean dose of 1,133/μl) and a lower circulating CD4+ lymphocyte count 37 mg/day. In all 7 cases, PCP occurred after the acute (370/μl) in 5 of 7 patients. However, three patients who had phase of interstitial pneumonia. Three patients were receiv- a CD4+ lymphocyte count of greater than 200/μl developed ing immunosuppressant therapy at the time of diagnosis of PCP. Six of the seven PCP patients had a high beta-D- PCP (two patients were receiving cyclosporine at 150 mg/ glucan level (range: 66.7-1,320 pg/ml, mean: 360 pg/ml). day, and one patient was receiving cyclophosphamide at 50 The three patients who had a CD4+ lymphocyte count of mg/day). greater than 200/μl and developed PCP are presented below 17 DOI: 10.2169/internalmedicine.47.0402 Figure 1. In ‘c’ and ‘d’ patchy, bilateral ground-glass opacity is seen, whereas it is absent prior to treatment, ‘a’ and ‘b’, respectively. (Tables 3, 4). prednisolone (40 mg/day). Four weeks after the beginning of A 69-year-old man (case No. 2) with microscopic poly- therapy, the
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